Curcuminoids have been shown to have significant potential in the medical management of chronic inflammatory diseases such as endometriosis. Currently only hormonal therapies including medroxyprogesterone acetate, GnRH-agonists, and danazol are available for the medical treatment of endometriosis. These hormonal treatments are often of limited efficacy and can elicit untoward side-effects due to suppression of endogenous steroid hormone levels. Our application addresses the pressing need for effective alternative endometriosis drugs that do not exhibit hormonal side-effects. We have shown that EF24, our most promising curcumin analog to date, suppresses endometriotic cell growth in an in vitro and in vivo model of endometriosis. Our long-term approach is to develop new endometriosis treatments with higher efficacy and fewer side effects. The overall goal of this grant is to test the mode of action of curcumin analogs on macrophage function, and test their efficacy in an in vivo animal model of endometriosis. This goal will be accomplished by two specific aims. In Aim 1, we will investigate the mechanism of action of curcumin analogs on macrophages. Mechanistic studies will be performed on peritoneal macrophages from thioglycollate treated mice to evaluate anti-inflammatory and antiangiogenic effects of curcumin analogs. In Aim 2, we will evaluate the effects of curcumin analogs on endometriosis in an in vivo model of endometriosis. Using an immunocompetent mouse model, we aim to investigate the effects of curcumin analogs on inflammatory and angiogenic responses of macrophages and on growth of endometriotic lesions. These studies should provide significant insight into the efficacy of curcumin analogs in an endometriosis model and identify novel therapeutic targets for future studies. It is our hope that knowledge gained from these preclinical studies will support the development of new drugs for clinical trials for women with endometriosis. PUBLIC HEALTH RELEVANCE: Endometriosis is a major public health issue. Standard endometriosis treatments are often of limited efficacy and can elicit untoward side-effects due to suppression of endogenous steroid hormone levels and therefore alternative treatments are needed. Knowledge gained from this work will support the development of new drugs for clinical trials for women with endometriosis.